A significant number of therapeutic targets reside inside cells and intracellular organelles. Therapeutics therefore must be able to gain access to cellular compartments, and be able to interact specifically with a given molecule to exert a desired effect. Many naturally occurring toxins perform such targeting with apparent ease, making them excellent paradigms for the delivery of therapeutics to the cell interior. By studying the mechanisms of cell entry, trafficking and modes of toxicity of these model delivery vectors, researchers can decipher how cells transport both endogenous molecules and exogenously applied therapeutics inside cells. Perhaps more importantly, the exploitation of cell binding and trafficking motifs could allow a therapeutic to target specifically, traffic within and escape from cellular compartments; in addition, toxic domains can be used to disrupt cell function specifically for therapeutic purposes. This review provides an overview of recent developments in the understanding of toxin targeting and trafficking, and discusses how these developments could result in opportunities for the design of more specific and efficient systems for therapeutic targeting.
Systems biology uses experimental and computational approaches to characterize large sample populations systematically, process large datasets, examine and analyze regulatory networks, and model reactions to determine how components are joined to form functional systems. Systems biology technologies, data and knowledge are particularly useful in understanding disease processes and drug actions. An important area of integration between systems biology and drug discovery is the concept of polypharmacology: the treatment of diseases by modulating more than one target. Polypharmacology for complex diseases is likely to involve multiple drugs acting on distinct targets that are part of a network regulating physiological responses. This review discusses the current state of the systems-level understanding of diseases and both the therapeutic and adverse mechanisms of drug actions. Drug-target networks can be used to identify multiple targets and to determine suitable combinations of drug targets or drugs. Thus, the discovery of new drug therapies for complex diseases may be greatly aided by systems biology.
Recent advances in the field of homogeneous asymmetric hydrogenation are presented in this review. An analysis of academic literature published in the past 2 years highlights significant advances in the asymmetric hydrogenation of functional groups that previously were considered difficult to hydrogenate, as well as the emergence of novel concepts in catalysis, such as the use of non-traditional metals, phosphine-free catalysts and chiral counterions. An analysis of industry publications from 2009 and 2010 highlights more established applications of asymmetric hydrogenation reactions; these are discussed with a particular focus on practical aspects, such as catalyst selection, experimental conditions and the removal of metal residues.
Heterocycles are ubiquitous structures in both drugs and natural products, and efficient methods for their construction are being pursued constantly. Carbon-hydrogen bond activation offers numerous advantages for the synthesis of heterocycles with respect to minimizing the length of synthetic routes and reducing waste. As interest in chiral medicinal leads increases, stereoselective methods for heterocycle synthesis must be developed. The use of carbon-hydrogen bond activation reactions for stereoselective heterocycle synthesis has produced a range of creative transformations that provide a wide array of structural motifs, selected examples of which are described in this review.
Allenamides are electron-deficient equivalents of allenamines, which can participate in a range of cycloaddition reactions giving rise to novel heterocycles and diverse molecular architectures similar to those contained in natural products. This review summarizes some of the research conducted in this field, with particular reference to predicting the stereochemical outcomes of such transformations. The applications of allenamides in cycloaddition transformations are highlighted, providing insight into the potential utility of this under-used synthon.
The discovery and development of pharmaceutical drugs targeting ion channels is important for treating a variety of medical conditions and diseases. Ion channels are expressed ubiquitously throughout the body, and are involved in many basic physiological processes. Neuronal ion channels are particularly appealing drug targets, and recent advances in screening ion channel function using optical-based and electrophysiological technologies have improved drug development in this field. Moreover, methods for the discovery of peptide-based neurotoxins and other natural products have proven useful in the pharmacological assessment of ion channel structure and function, while also contributing to the identification of lead molecules for drug development.
Gene therapy holds considerable promise for the treatment of cardiovascular disease and may provide novel therapeutic solutions for both genetic disorders and acquired pathophysiologies such as arteriosclerosis, heart failure and arrhythmias. Recombinant DNA technology and the sequencing of the human genome have made a plethora of candidate therapeutic genes available for cardiovascular diseases. However, progress in the field of gene therapy for cardiovascular disease has been modest; one of the key reasons for this limited progress is the lack of gene delivery systems for localizing gene therapy to specific sites to optimize transgene expression and efficacy. This review summarizes progress made toward the site-specific delivery of cardiovascular gene therapy and highlights selected promising novel approaches.
The four isoforms of class I phosphatidylinositol-3-kinase (PI3K) were originally thought to be redundant in function; however, further research and new technologies have revealed that each subunit has distinct characteristics. In the past decade the number of PI3K inhibitors has increased from a few agents with unacceptable promiscuity and pharmacological properties, to a family of selective agents that are either progressing through experimental development or are in clinical trials. These agents, with two notable exceptions, target multiple members of the PI3K class I isoforms. As data become increasingly available, the concept that inhibiting a single PI3K isoform may offer improved therapeutic benefit, while eliminating the potentially negative effects of pan-isoform inhibition, is driving efforts to develop more specific inhibitors. However, questions remain regarding the best isoform to inhibit for maximum benefit in different pathological settings, and whether increased specificity may lead to a loss in efficacy as a result of isoform redundancy in some settings. This review discusses the current understanding of individual PI3K isoforms in physiology and pathological states, as well as the status of PI3K inhibitors in preclinical and clinical development.
Infusion reactions and cytokine release syndrome (CRS) are an emerging issue in drug development and are of particular importance with the development of new therapeutic proteins. Increasing concerns regarding patient safety require a better understanding of the mechanism involved and the development of novel methods for preventing and predicting such reactions and CRS. This review discusses developments during the past few years in understanding the mechanisms that cause infusion reactions and CRS, advances in approaches to prevent CRS, the reason why preclinical animal models are unreliable predictors of CRS, and new developments in the design and analysis of in vitro screening systems for the prediction of CRS.
The liver X receptors LXRalpha and LXRbeta regulate the expression of genes promoting cellular cholesterol efflux and the formation of HDL particles, and are atheroprotective. However, LXRalpha and LXRbeta also regulate the expression of genes involved in lipogenesis and hypertriglyceridemia. The identification of efficacious LXR modulators that are devoid of undesirable side effects remains a significant challenge for drug development. The X-ray structures of many LXR protein/small-molecule complexes have revealed that the ligand-binding pockets of LXRalpha and LXRbeta, despite being highly conserved, are large and flexible; these properties have allowed the design of a wide range of ligands with varied selectivity profiles. This review discusses the latest medicinal chemistry strategies used to derive novel LXR modulators with the potential for enhanced therapeutic utility and safety, and summarizes the current status of compounds that have progressed into clinical development.
Traditional Chinese medicine (TCM) is a holistic approach to health that attempts to bring the body, mind and spirit into harmony. TCM is an essential part of the healthcare system in several Asian countries, and is considered a complementary or alternative medical system in most Western countries. An integration of the traditional Chinese and Western systems of medicine has begun in multiple medical centers internationally, and there is increasing evidence that several herbs and combinations of herbs used in TCM impart important pharmacological effects. The number of databases and compilations of herbs, herbal formulations, phytochemical constituents and molecular targets is increasing, primarily because of the widespread use of TCM in combination with Western drugs. The continued popularity of herbal remedies worldwide suggests that evidence-based research in this field, as well as information regarding the potential efficacy and safety of phytochemical constituents in herbs and TCM formulations, are essential, particularly when TCM is used in combination with other drugs. Herb-drug interactions are similar to drug-drug interactions in terms of their effects on ADME properties. Improvements in the knowledge of the molecular targets and metabolic pathways, as well as of the synergistic and inhibitory effects associated with important phytochemicals from herbs and herbal formulations, will lead to the development of rational approaches for the safe combination of healthcare systems from different cultures.
The cloning of the three tachykinin receptors in the late 1980s formed the basis of intense preclinical research efforts into the systems relating to the tachykinin receptors, as well as compound screening campaigns. Remarkably, orally active non-peptide antagonists were successfully identified for all three of the tachykinin receptors, providing tools for further evaluation of the pharmacology of these receptor systems. The NK3 receptor ( mammalian tachykinin receptor 3), which exhibited a discrete expression pattern and the modulatory regulation of various transmitter systems in the CNS, has attracted significant interest. Preclinical studies demonstrated that the NK3 receptor might be a promising target for CNS disorders, and clinical trials with non-peptide NK3 receptor antagonists have been performed for indications such as schizophrenia, major depressive disorder, panic attacks and Parkinson's disease. In particular, the positive results of the schizophrenia meta-trial with osanetant increased the focus on the NK3 receptor system and its clinical potential. Consequently, a significant number of patents covering non-peptide antagonists for the NK3 receptor have been published during the past decade. This review describes the most recent NK3 receptor antagonists (published from 2004 to 2009), which are classified into seven unique templates.
Since 2008, significant advances have been made in understanding the role of diacylglycerol acyl transferase-1 (DGAT1) in disease states such as diabetes and obesity. Gene deletion and overexpression studies have provided important new insights into the function of DGAT1, as have the first reports from preclinical models of small-molecule inhibitor effects, which are discussed in this review in relation to the phenotypes of DGAT knockout and overexpression models. The progress of medicinal chemistry efforts has resulted in a new generation of DGAT1 inhibitors that have progressed into clinical development, with the leading compound LCQ-908 (Novartis AG) now in phase II clinical trials. This exciting progress has led researchers to anticipate that an understanding of the human pharmacology of DGAT1 inhibitors, as well as their potential as therapeutic agents for the treatment of diabetes and obesity, will be achieved in the next few years.
Vasopressin (also known as arginine vasopressin [AVP]) is a small cyclic peptide that acts at the V1a, V1b and V2 GPCRs to regulate a wide range of physiological functions, including vasoconstriction, smooth muscle contractility, response to stress, and excretion of water and sodium via the kidney. The potential therapeutic applications of AVP receptor ligands have prompted significant interest in this target within the pharmaceutical research community, and several small-molecule drugs targeting the AVP receptor have reached the market, mainly for cardiovascular indications. The development of AVP receptor modulators for the treatment of CNS indications has proven more challenging, and is the focus of this review. The regulatory role of AVP on the hypothalamic-pituitary-adrenal (HPA) axis suggests potential uses for AVP receptor modulators in various CNS indications, including depression, anxiety and post-traumatic stress disorder. Several clinical trials of V1a and V1b receptor antagonists in CNS indications have been conducted, but none of these drugs have reached the market. In recent years, the discovery of the key role of AVP in modulating complex social behaviors has provided a unique opportunity to understand the physiological mechanisms of social interactions. Ultimately, the ongoing research in this field may enable the development of treatments to alleviate the social deficits associated with conditions such as autism and schizophrenia. Given the large unmet medical need in these areas, a renewed interest in the field of CNS-penetrant AVP receptors modulators is expected.
A significant number of therapeutic targets reside inside cells and intracellular organelles. Therapeutics therefore must be able to gain access to cellular compartments, and be able to interact specifically with a given molecule to exert a desired effect. Many naturally occurring toxins perform such targeting with apparent ease, making them excellent paradigms for the delivery of therapeutics to the cell interior. By studying the mechanisms of cell entry, trafficking and modes of toxicity of these model delivery vectors, researchers can decipher how cells transport both endogenous molecules and exogenously applied therapeutics inside cells. Perhaps more importantly, the exploitation of cell binding and trafficking motifs could allow a therapeutic to target specifically, traffic within and escape from cellular compartments; in addition, toxic domains can be used to disrupt cell function specifically for therapeutic purposes. This review provides an overview of recent developments in the understanding of toxin targeting and trafficking, and discusses how these developments could result in opportunities for the design of more specific and efficient systems for therapeutic targeting.
TOR (target of rapamycin) is a serine-threonine protein kinase that is conserved across a diverse range of species from fungi to mammals. The signaling pathway that is anchored by TOR is also conserved across species. In mammals, mTOR integrates growth factor, amino acid, nutrient and energy sensing signals, and thus plays a major role in cell growth and proliferation, protein synthesis and autophagy. As a result of the pivotal role of mTOR in signaling, the aberrant regulation of mTOR has been implicated in several disease processes, including cancer, diabetes, ocular diseases and neurodegenerative disorders, as well as in lifespan extension. More recently, rapamycin (sirolimus) analogs that antagonize the mTOR signaling pathway have been approved for the treatment of several cancers. This review describes some recent advances in the understanding of mTOR signaling, with an emphasis on the functional consequences of mTOR inhibition and therapeutic intervention strategies.
The core histones H2A, H2B, H3 and H4, undergo various post-translational modifications, such as acetylation, methylation and phosphorylation. Core histone phosphorylation has roles in several biological responses, including transcription, mitosis, DNA repair and apoptosis. Histone phosphorylation may disrupt chromatin structure and/or provide a 'code' for the recruitment or occlusion of non-histone chromosomal proteins to chromatin. Among the better-characterized histone phosphorylation events are the phosphorylation of H3 at Ser10 and Ser 28, and the phosphorylation of the H2A variant H2A.X at Ser139. Much remains to be learned about the function of the many other core histone phosphorylation events in chromatin. This review provides an overview of the biological roles of core histone phosphorylation in mammalian cells.
Cytochrome P450 (CYP) is a large family of well-conserved integral membrane proteins localized primarily in the membrane of the endoplasmic reticulum (ER), where these enzymes metabolize a variety of both endogenous and exogenous compounds. It has become apparent that these microsomal CYP proteins are also present in other cellular compartments, such as the cell surface and in mitochondria, where the enzymes display catalytic activity toward CYP-specific substrates, in some cases with altered substrate specificity. CYP-drug adducts exposed at the cell surface are important mediators of idiosyncratic drug toxicities. Therefore, understanding the molecular mechanisms responsible for directing these microsomal CYPs to other, non-ER cellular compartments is important. These alternatively localized CYPs should be considered as possible drug targets and as important factors during drug discovery and development, as the detoxification capacity is lower in the compartments where such CYP proteins are located. This review discusses the mechanisms of intracellular CYP transport, and the implications of the presence of CYP proteins in extra-ER compartments for drug metabolism and toxicity.
As the most prevalent form of dementia worldwide, Alzheimer's disease (AD) continues to be a burden for patients and their families. In addition, with the global population of aged individuals increasing exponentially, AD represents a significant economic burden to society. The development of an effective approach for the treatment of AD is thus of major importance, as current treatment strategies are limited to agents that attenuate disease symptomatology without addressing the causes of disease. A considerable need exists for the development of an effective therapy to prevent, or at least delay, the progression of AD. Current hypotheses for the pathogenesis of AD are discussed in this review, with a particular emphasis on the implications of these hypotheses with respect to treatment strategies and preventive measures.
